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SCIENTIFIC TEAM - 1 الفريق العلمي

Therapeutic Uses of Neuromuscular Blockers

◆Main Therapeutic Use: Adjunct to General Anesthesia

عة كبیرة من الاثناء التخدیر الكلي عشان ما اعطي جر اعدكمسلاستخدام الرئیسي ا◆

.general anesthetics

◆Muscle relaxation: orthopedic, abdominal surgeries

و خاصة عملیات البطن والعظام relaxant muscle في اي عملیة بنحتاج◆

◆Facilitation of intubation, mechanical ventilation

ها وهذا الشي شائع الان لأنventilator mechanical المیكانیكیة التهویة تسهیل-◆

COVID-19تستخدم للحالات الصعبه لمرض

◆Succinylcholine during electroconvulsive therapy

.بهالحالة بنستخدمه كثیر مش( convulsions) العضلات تشنجات تقلیل◆-

RSI: Rapid Sequence Intubation

tracheal tube .وضع تسهیل

rapid sequence induction and intubation

او (succinylcholine و بعدین anesthetics الي هو ketamine و بعدین oxygen اول اشي بنعطیه

(rocuronium و بعدین بتحط) tube دقائق ١٠ كل العملیة بتستغرق(

◆ Preferred method of endotracheal tube

intubation (ETTI) at the ER

◆ results in rapid unconsciousness

(induction) and neuromuscular blockade

(paralysis)

◆ Give ketamine → followed by

succinylcholine (alternative rocuronium).

Lecture 6


Cholinergic Agonists

okay so next we will be discussing a separate group of drugs that are called indirect

cholinergic agonists meaning that these drugs provide cholinergic activity but in an indirect

way and these can be either reversible or reversible anti-colonoscopies agents

Myasthenia Gravis

◆ Rare, autoimmune disorder

◆ Autoantibodies directed against the muscle-

nicotinic acetylcholine postsynaptic receptors

specifically in the neuromuscular junction

◆ Fatigable muscle weakness that worsens with

activity

◆ Ptosis(dropping of the eyelid because of

weakness in the upper eyelid muscles )

◆sometimes Myasthenia Gravis can be severe enough to result in the paralysis of respiratory

muscles and in this case the patient is at risk of respiratory failure and death

كیف بدنا نعالجه؟ ◆

synapse داخل ال ability Achبنعطي ادویة تزود ال

عنا نوعین من الادویة◆

-Direct agonist

بس ما حنحكي عنهم R nicotinic بتشتغل عال

-Indirect agonist

parasympathetic و ganglia autonomicالموجود في ال AchE بتثبط ال R ما بتشتغل ع ال

NMJ و innervation فاله. less specific effect

Indirect-acting Cholinergic Agonists: Anticholinesterase

Agents (Reversible)

• AChE cleaves ACh to acetate and choline

• Inhibition of AChE results in____________??

Increase Ach

• Which receptors are affected?

• Anti-AChE agents are either short- or intermediate acting


Edrophonium

• Short-acting

• Reversibly binds to the active site of AChE - - - -» increase Ache

• Rapid onset: 1-2 minutes

• Short duration: 10-20 minutes

• Used in the diagnosis of myasthenia gravis (Tensilon test)

• Used to reverse the effects of NMJ blockers

•It’s use is limited because it does not have therapeutic save profile

• Excess drug → cholinergic crisis (what is the antidote)?

• Cholinergic crisis means increase of Ach in gap junction and over

stimulation

• The antidote is Atropine

Physostigmine

• Found naturally

• Substrate for AChE; forms stable intermediate with the

enzyme (reversible)

• Stimulates nicotinic receptors both N and M

• Used in autonomic NS

• Benet rate BBB

• Very bulky

• Stimulate both muscarinic and nicotinic receptor in the

ANS and peripherally

• Duration of action: 30 mins to 2 hours

• Used to increase intestinal/bladder motility

( have parasympathetic effect)

• Used to treat atropine overdose

(because atropine increase HR and Heart contractility)

• Possible adverse effects?

• Contraction of visceral sooth muscle • Bradycardia • Hypotension • Miosis

• Convulsion


Neostigmine

• Synthetic , very large drug

• Reversible AChE inhibitor

• Poorly absorbed from GI; does not cross BBB.

Which means? Its effect is peripheral

• Similar duration of action as physostigmine

• Used to stimulate gut/bladder

• Used as antidote for NMJ blockers

• Used for myasthenia gravis

• Can you use neostigmine to treat atropine overdose?

it is not a good choice because it is poorly absorbed and does not cross BBB

•Parasympathetic like side effects


Pyridostigmine

• AChE inhibitor

• Used for the chronic management of myasthenia gravis

• Duration of action: intermediate 3 to 6 hours

• Is the best to treat chronic Myasthenia Gravis Because it has a longer duration than others

and can be given less frequently

Indirect-acting Cholinergic Agonists: Anticholinesterase Agents

(Irreversible)

• Organophosphates

• Longer increase in junctional Ach

Echothiophate

• Organophosphate

• Covalently binds a phosphate group at the active site of AChE

• Phosphorylated AChE releases one of its ethyl groups (aging)

• Impossible for chemical activators such as pralidoxime to break bond between drug and

enzyme

• Uses: cholinergic activation, muscle paralysis, ophthalmic uses

MOA of this drug has 2 steps :

1st step is binding of drug via its phosphate group at the active side of AchE this causes

phosphorylation of the enzyme and until now its reversibly inactivated that means if the drug

pralidoxime cameto reverse the action if he drug it can work by breaking the phosphate bond

2nd step called aging ----» release of ethyl group from phosphorylated AchE right now the

enzyme became irreversibly inhibited and thre drug pralidoxime cant work


How about some toxicology?

• Irreversible AChE inhibitors (organophosphates)

are used as insecticides

• Possibility for accidental poisoning

• Suicide/homicide

• Warfare/chemical terrorism (nerve gas)

Reactivation Of Acetylcholinesterase

Pralidoxime

• reactivate inhibited AChE

• displaces the phosphate group of the organophosphate (e.g., echothiophate)and regenerates

the enzyme

• Does not cross BBB. What does this mean?

That means it can only be used to reverse the action of the enzyme if it was in the reversiable

stage and peripheral

• Would it overcome the toxicity of reversible AChE inhibitors?

Pharmacological antidote for oregano phosphate is Atropine because it’s action on the

receptor not the enzyme and can cross CNS.

QUESTION

A 44-year old male patient works as an ICU nurse at a university hospital. He was brought to

the emergency room suffering from unconsciousness, muscle paralysis and severe apnea.

The patient has a history of severe depression and previous suicidal attempts. After

successful intubation the patient was further examined to determine the cause of his

condition and his muscles were found to respond to direct electrical stimulation. Which of

the following drugs might be useful to give this patient immediately?

<A>Atropine

<B>Neostigmine

<C>Succinylcholine

<D>Acetylcholine

<E>Rocuronium ANSWER IS B


QUESTION

Which of the following scenarios will mostly attenuate the neuromuscular blockade of

cisatracurium?

<A>If cisatracurium was administered with atropine simultaneously.

<B>If cisatracurium was administered after succinylcholine.

<C>If cisatracurium was administered with gentamicin simultaneously.

<D>If cisatracurium was administered with desflurane simultaneously.

<E>If cisatracurium was administered before physostigmine

ANSWER IS E

- - - - - - - - - - - -

Skeletal Muscle Relaxants

Overview

• Low back pain is ranked amongst top causes of

pain

• Mainstay of symptomatic treatment includes

NSAIDs and acetaminophen (paracetamol)

• Skeletal muscle relaxants are an alternative

Subdivided into central which acts on brain and

peripheral which used for pain associated with neuron disorders as multiple sclerosis

Muscle Relaxant Use

• Used more than expected

• 35% of patients use muscle relaxants for

nonspecific back pain and of those, 18.5% use them

as first-line

• Make up 45% of total prescription for

musculoskeletal pain

• Conflicting evidence of their benefits and adverse

effects

• Short-term vs. long-term use


Baclofen

• Chemistry: structurally similar to γaminobutyric

acid (GABA)

• MOA: GABAB agonist→ Inhibits transmission

at spinal level → CNS depression

• Indications: MS, spinal chord lesions

• Kinetics: oral or intrathecal

• Adverse Effects: drowsiness, fatigue, nausea,

dose adjustment in renal disease

Ach is a stimulatory neurotransmitter once it binds to post synaptic receptor it cause AP. But

GABA is an inhibitory molecule binds to 2 receptors GABAa or GABAb

GABAa - - -» is a ligand gated ion channel, allows Cl- to go inside which lead to increase

the negativity of the membrane and become difficult to be stimulated.

GABAb----» is a G-protein signalling pathway its effect is CNS depression.


Dantrolene

Anti Spasticity

• Chemistry: structurally related to phenytoin

• MOA: Inhibits Ca+2 release from

sarcoplasmic reticulum in skeletal myocytes

• Indications: MS, CP, malignant hyperthermia

• Adverse Effects: risk of hepatotoxicity, not

used for low back pain

Tizanidine

• Chemistry: related to clonidine

• MOA: α2 -adrenergic agonist→ presynaptic inhibition

of motor neurons/excitatory interneurons

• Indications: MS, Spinal chord disease & hypertension

• Adverse Effects: dry mouth, somnolence, hypotension,

avoid in hepatic impairment

Alfa 2 receptor is found on presynaptic

membrane, it’s function is to bound with

excessive NE and decrease the production

of neurotransmitters and decrease motor

signalling


Orphenadrine

Antihistamines

• Chemistry: analog of diphenhydramine

• MOA: antimuscarinic (central atropine-like effects)

• Indications: muscle spasm, Parkinson's disease

• Adverse Effects: Dry mouth, urinary retention, blurred

vision, mydriasis

Carisoprodol

• Chemistry: analog of diphenhydramine

• MOA: unknown. CNS depression?

By binding to GABA b

• Indications: acute treatment of musculoskeletal

pain

• Adverse Effects: possible abuse potential

(due to GABAA modulation)

Cyclobenzaprine

• Chemistry: similar to tricyclic antidepressants (TCA)

• MOA: reduces tonic somatic motor activity (alpha

and gamma motor neurons), others similar to TCA

• Indications: acute treatment of musculoskeletal pain,

muscle spasm

• Adverse Effects: drowsiness, dry mouth

Metaxalone

• MOA: General CNS depression, sedation, no direct

effect on muscles

• Indications: acute treatment of musculoskeletal pain,

muscle spasm

• Adverse Effects: GI disturbance, nausea, vomiting,

dizziness


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